CN102439018A - Fosfluconazole derivatives, synthesis, and use in long acting formulations - Google Patents

Fosfluconazole derivatives, synthesis, and use in long acting formulations Download PDF

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CN102439018A
CN102439018A CN2010800222914A CN201080022291A CN102439018A CN 102439018 A CN102439018 A CN 102439018A CN 2010800222914 A CN2010800222914 A CN 2010800222914A CN 201080022291 A CN201080022291 A CN 201080022291A CN 102439018 A CN102439018 A CN 102439018A
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compound
formula
fluconazole
base
group
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Y·R·J·P·戈尼森
J·F·M·沃尔斯波尔斯
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SEPS Pharma NV
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Priority claimed from GB0904706A external-priority patent/GB0904706D0/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having three nitrogen atoms as the only ring hetero atoms
    • C07F9/6518—Five-membered rings

Abstract

The invention relates to a compound of formula (I) and the salts, N-oxides, quaternary amines, and stereoisomers thereof, wherein R1 to R8 are as defined in the claims. The invention further relates to intermediates and methods for the preparation of the compounds of formula (I). The invention also relates to the compounds of formula (I) for use as a medicament, particularly for the prevention or treatment of fungal infections.

Description

Good fortune department fluconazole verivate, the synthetic and purposes in prolonged action preparation
Invention field
The present invention relates to organic chemistry, particularly prodrug and pharmaceutical prepn.
Background of invention
Fluconazole; Be also referred to as Fluconazole (Diflucan ); Be a kind of triazole anti-fungal agents, at first be described in the UK patented claim 2099818 (Pfizer Limited).It is used for treatment in the whole world because candidiasis, cryptococcus and pathogenic yeast of other condition (opportunistic yeast) or fungus-caused infection.This medicine can be used as tablet (50,100 or 200mg), oral suspensions and intravenous injection (200 or 400mg) and utilizes.When being used to treat the invasive moniliosis for example bloodstream infection, deep tissue position or other normal sterile region infect; The first loading dose that gives fluconazole is 800mg (oral or intravenous injection), and then a day maintenance dose is 400mg (oral or intravenous injection).800mg or above higher per daily dose can use (J.Infect.1993 under situation about selecting; 16:133-146.Clin.Infect.Dis.2004; 38:161-189.Clin.Infect.Dis.2003; 36:1221-1228.Eur.J.Clin.Microbiol.Infect.Dis.1999,18:165-174).
SULPHOSUCCINIC ACID ESTER is widely used in preparing the water miscible prodrug that supplies intravenous administration.Its prodrug of SULPHOSUCCINIC ACID ESTER, particularly good fortune department fluconazole (fosfluconazole) or Prodif
Figure BPA00001464278600012
of the open fluconazole of patented claim WO9728169 (Pfizer) carries out esterification by the hydroxyl of fluconazole and phosphoric acid and produces.In vivo, its quick hydrolysis and demonstrate the clinical effect that is equal to fluconazole.The SULPHOSUCCINIC ACID ESTER esterification of fluconazole makes this compound in the aqueous solution of pH 4-12, have high solubleness.Giving the 400mg fluconazole in the past must the 200mL volume, and the good fortune department fluconazole that is equal to the 400mg fluconazole only needs 5mL solution, has reduced 40-on the volume doubly, so has allowed bolus injection.In suffering from the mycotic patient of the deep-seated that needs the high dosage anti-mycotic agent, carry out multiple pharmacological agent and adjuvant therapy together, like fluid infusion.But in concurrent serious obscure disease, particularly among the patient of heart failure, respiratory insufficiency or ascites, fluid infusion possibly be confined to adjust cylinder water content and electrolytical balance.Compare with fluconazole, good fortune department fluconazole is easy for deep-seated mycosis patient, because it can pass through the bolus injection administration, thereby significantly reduces volume load.(Japanese?Pharmacology&Therapeutics?2005，33(4)，267-302)。
Keep effective treatment of the serious restriction of metering fungi infestation the every day of fluconazole.This administration schedule causes the higher working load of clinical staff and the more important thing is, therefore patient's compliance of difference has increased the possibility that gives suboptimal dose, finally causes occurring the appearance of resistance fungi strain.Confirmed the reduction of medicine target approach enzyme (fungal cell's pigment P-450-dependent enzyme lanosterol 14-α-demethylase), be one of mechanism that in Candida albicans, produces resistance (Clin.Microbiol.Rev.1999,12:501-517).Likewise; The inferior therapeutic dose (promptly＜400mg/ day) that Candida glabrata (C.glabrata) is exposed to fluconazole can cause not only to fluconazole also to the resistance of other azole (being itraconazole and Vorionazole) (Antimicrob.Agents Chemother.2005,49:783-787).Notice with also attracting people's attention the coding target enzyme gene ERG11 cross to express the said target enzyme that causes producing high density, produce fluconazole concentration in the higher born of the same parents to suppress the needs of enzyme molecule all in the cell.
When patient's compliance was problem, the formulation of long-acting dosage was a possible solution, and wherein single-dose causes in the period that prolongs, continuing to discharge medicine.Therefore this formulation has been simplified the dosage regimen that needs of patients is observed, and has reduced the possibility of not complying with that occurs when using more accurate dosage regimen.A kind of in these formulations is storage storehouse (depot) preparation, and it can comprise intramuscularly with various administrations.Prepare storage storehouse dose ejection agent, slowly absorb the drug, can keep treatment level a few days or several weeks at patient's whole body usually at every turn to provide from medicine-feeding part.
Storage storehouse dose ejection agent has cost.The volume of injection is big more, and pain is just got in injection.(Ann Pharmacother.1996 such as Jorgensen; 30 (7-8): 729-32) shown mutual relationship between pain and the subcutaneous injection volume, volume is that 1-1.5mL is that 0.5mL or following comparing cause significantly pain more with volume.Therefore, require as far as possible the volume of injecting to be minimized.
Patented claim WO05006860 (The Board of Governors for Higher Education State of Rhode Island and Providence Plantations) discloses the phosphotriester that is connected in Fatty Alcohol(C12-C14 and C12-C18).
(Bioorg Med Chem.2004 December 1 such as Nguyen-Hai Nam; 12 (23): 6255-69) synthetic and estimated the Fatty Alcohol(C12-C14 and C12-C18) and the glucide SULPHOSUCCINIC ACID ESTER of fluconazole.
An object of the present invention is to provide fluconazole verivate and preparation, it sends this medicine being effective to treat under the Mammals concentration of (comprising the people) in the time durations that is continuing.These fluconazole forms and preparation must be safe, promptly have minimum spinoff and have suitable pharmaceutical kinetics to distribute.
An object of the present invention is to provide fluconazole verivate and preparation, it can improve one or more following pharmacokinetic parameter with respect to current available preparation: long transformation period, increase volume of distribution, prolong drug release, persistent plasma concns or long acting duration.
An object of the present invention is to provide when comparing with current available formulation is the fluconazole verivate and the preparation of high loading dosage.
An object of the present invention is to provide the chemically stable verivate of fluconazole.Another object of the present invention provides the chemically stable preparation of fluconazole.A further object of the invention provides the soluble derivative of fluconazole.
The agent number of the fluconazole that an object of the present invention is to give minimizes.An object of the present invention is to provide the fluconazole verivate or the preparation that allow bolus injection.Another object of the present invention is the storage storehouse that fluconazole is provided in the patient.
An object of the present invention is to provide the fluconazole injectable formulation of the proper volume of avoiding the pain administration.
An object of the present invention is to provide and to reduce fluconazole verivate and the preparation that the strain of resistance fungi occurs.
An object of the present invention is to provide the fluconazole verivate and the preparation that can increase fluconazole concentration in the cell.
Summary of the invention
The inventor is surprised to find some good fortune department fluconazole verivate with the solubleness distribution that attracts people's attention and in some lipophilic solvent, demonstrates valuable high-dissolvability.Particularly, some good fortune department fluconazole verivate height of the present invention is suitable for lipid formulation and injectable depot formulations.These preparations even after administration, all demonstrate effective plasma concns in 2 months.In addition, the present invention is with to the patient with clinical staff all makes things convenient for the mode of administration to reach this final desired increase drug load and prolongation is sent.
The present invention relates to a kind of formula (I) compound and salt thereof, N-oxide compound, quaternary amine and steric isomer:
Figure BPA00001464278600041
Wherein:
R 1Be hydrogen or C 1-6Alkyl;
R 2Be the gonane base or be selected from following group
Figure BPA00001464278600042
Symbol
Figure BPA00001464278600043
Represent C 2-6Alkylidene group (alkanediyl);
R 3, R 4And R 5Independently be C separately 6-18Alkyl or gonane base; With
R 6, R 7And R 8Independently be C separately 1-6Alkyl.
The invention still further relates to the method for preparing formula (I) compound, its salt and stereochemistry heterogeneous forms, and relate to the midbody that uses among these preparing methods.
The invention still further relates to formula (I) compound itself, its salt, N-oxide compound, quaternary amine and stereochemistry heterogeneous forms as medicine.The invention still further relates to medicinal compsns, it comprises specific formula (I) compound of this paper of pharmaceutically acceptable carrier and significant quantity.
The invention further relates to above-mentioned compound, compsn and medicinal compsns and be used to prepare the medicine of prevention or treatment fungi infestation.Perhaps express in other words, the present invention relates to be used to prevent or treat compound, compsn and the medicinal compsns of fungi infestation.Similarly, the present invention relates to the method for a kind of prevention or treatment fungi infestation, compound as herein described, compsn and the medicinal compsns of the patient's significant quantity through needing it.
The invention still further relates to and a kind ofly improve the fluconazole lipotropy or prolong that fluconazole discharges or the method for pharmacological activity, this method comprises fluconazole is converted into formula (I) compound or its pharmacy acceptable salt.
The invention further relates to formula (VI) chemical group as the purposes of introducing group (promoiety)
Figure BPA00001464278600051
R wherein 1And R 2Separately by above definition; With
Combining of the Sauerstoffatom of wavy line (
Figure BPA00001464278600052
expression) representative and medicine.
Description of drawings
Fig. 1: (2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base ethyl (3S, 8R, 9S; 10R, 13S, 14S, 17R)-10,13,17-trimethylammonium-17-((R)-6-methylheptane-2-yl)-2,3; 4,7,8,9,10,11; 12,13,14,15,16, the fusing point characteristic that 17-ten tetrahydrochysenes-1H-cyclopenta-[a] phenanthrene-3-base SULPHOSUCCINIC ACID ESTER is measured through dsc (DSC)
Fig. 2: 2-((2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base oxygen base) (oxyethyl group) phosphorus acyloxy) ethyl (3S, 8R, 9S; 10R, 13S, 14S, 17R)-10,13,17-trimethylammonium-17-((R)-6-methylheptane-2-yl)-2,3; 4,7,8,9,10,11; 12,13,14,15,16, the fusing point DSC characteristic of 17-ten tetrahydrochysenes-1H-cyclopenta-[a] phenanthrene-3-base succinate
Detailed Description Of The Invention
The present invention relates to a kind of formula (I) compound and salt thereof, N-oxide compound, quaternary amine and steric isomer:
Figure BPA00001464278600061
Wherein:
R 1Be hydrogen or C 1-6Alkyl;
R 2Be the gonane base or be selected from following group
Figure BPA00001464278600062
Symbol
Figure BPA00001464278600063
Represent C 2-6Alkylidene group;
R 3, R 4And R 5Independently be C separately 6-18Alkyl or gonane base; With
R 6, R 7And R 8Independently be C separately 1-6Alkyl.
Removing other has explanation, like preceding text and institute's time spent hereinafter, adopts following definition.
" C as group or part group used herein 1-4Alkyl " be defined as the straight or branched stable hydrocarbon group with 1-4 carbon atom, for example methyl, ethyl, 1-propyl group, 2-propyl group, 1-butyl, 2-butyl, 2-methyl isophthalic acid-propyl group.
" C 1-6Alkyl " comprise C 1-4Alkyl group and have the more high-grade homologue of 5 or 6 carbon atoms, for example 1-amyl group, 2-amyl group, 3-amyl group, 1-hexyl, 2-hexyl, 2-methyl-1-butene base, 2-methyl-1-pentene base, 2-ethyl-1-butyl, 3-methyl-2-amyl group etc.C 1-6That pay close attention in the alkyl is C 1-4Alkyl.
" C as group or part group 6-18Alkyl " be defined as straight or branched stable hydrocarbon group with 6-18 carbon atom; for example heptane base, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, 4,8-dimethyl-hexadecyl, 4-ethyl-11-methyl pentadecyl, 5-butyl dodecyl etc.
C 3-7Naphthenic base is the full name of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.
Term " C 2-6Alkylidene group " definition and corresponding " C 2-6Alkyl " identical, but be divalence but not monovalence.Like this, divalence C 2-6Alkyl is defined as the saturated divalent hydrocarbyl mission of the straight or branched with 2-6 carbon atom, as 1, and 2-second two bases or ethylene, 1,3-glyceryl or 1; 3-propylidene, 1,2-glyceryl or propylene, 1,4-fourth two bases or tetramethylene, 1; 3-fourth two bases or 1,3-butylidene, 1,2-fourth two bases or 1,2-butylidene, 1,5-penta 2 bases or 1; 5-pentylidene, 1,6-dihexyl or hexamethylene etc. also comprise alkylidene group, like ethylidene, propylidene etc.
Term " gonane base " refer to steroid class and sterol group the two; Its oxygen or carbon atom with formula (I) compound combines; This situation possibly be that through the particular carbon atom combination that has hydroxyl in the 4-ring gonane structure, it is terminal that said hydroxyl does not come across formula (I) compound.
Term " steroid class " refers to polynuclear compound, and it has the common parent nucleus, and it is condensed, reductive 17-carbon atom ring system, the perhydrocyclopentanophenanthrene of formula (VII).
Figure BPA00001464278600081
In one embodiment, steroid class group has two methyl and the aliphatic lateral chain that is connected with parent nucleus (from the Condensed Chemical Dictionary (final minification chemistry dictionary) of Hawley, the 11st edition).In one embodiment, steroid class group is formula (VIII) group, and wherein the wavy line representative is connected to the key in formula (I) compound.
Term " sterol " refers to that the steroid class and the skeleton that on C-3, have hydroxyl are cholestane mostly.Other carbon atom can be present in (IUPAC Steroid Nomenclature (steroid nomenclature), 1987) in the side chain.
Particularly, term " gonane base " comprises the group form of following compound: Ah manys' sterol (adosterol); The cholecalciferol class is like hydroxycholecalciferol (U-32070E, dihydroxycholecalciferol, 24, the two hydroxyvitamin D of 25- 3, CALCITRIOL USP); Cholesterol is like SUV itself, 19-Iodocholesterol, diazasterol, Dihydrocholesterol, cholesteryl ester, aphyllidine (desmosterol), hydroxycholesterol oxycholesterol, ketocholestrol; Dihydrotachysterol; Viosterol is like 25-hydroxy-vitamin D 2Fusidic acid; Lanosterol; Plant sterol is like the steroidal of casting off a skin, ergosterol (whitanolide (liquor-saturated eggplant lactone)), Sitosterol, Stigmasterol; Cycloartenol; Zoosterol; And verivate.As a term used herein instance, the group form of SUV is referred to herein as cholesteryl.The group form of Dihydrocholesterol is referred to herein as the cholestane base.
In following table 1, provide the sterols of concern and the chemical structure of steroid class.
Table 1
Figure BPA00001464278600083
Figure BPA00001464278600091
Figure BPA00001464278600101
Figure BPA00001464278600111
It should be noted group position on any molecular moiety used in the definition can be on this part Anywhere, as long as it is chemically stable.When any variable occurs when once above in any part, definition separately is independently.Used group comprises all possible isomer in the definition of variable, except as otherwise noted.For example, amyl group comprises 1-amyl group, 2-amyl group and 3-amyl group.
When hereinafter using a technical term " formula (I) compound " or " The compounds of this invention " or similar terms, it means and comprises formula (I) compound, its salt and its stereochemical isomeric form.
Formula (I) compound can have several chiral centres, particularly works as R 2Or R 3When being the gonane base, and exist with stereochemistry heterogeneous forms." stereochemistry heterogeneous forms " used herein be defined as that formula (I) compound can have, combine identical atom to form by the key through identical sequence, but all possible compound with different not interchangeable three-dimensional structures.For wherein using (R) or (S) in the name substituting group under the situation of absolute configuration of chiral atom, this name is considered is entire compound but not isolated substituting group.
Except that other mentions or explains, the chemical name of compound comprise that said compound possibly have might stereochemistry heterogeneous forms mixture.Said mixture can contain all diastereomers and the enantiomorph of the basic molecular structure of said compound.Form that all stereochemistry heterogeneous forms of The compounds of this invention are pure or mixture each other all are intended to be encompassed within the scope of the present invention.
The pure stereoisomeric forms in any ratio of compound that this paper mentions and midbody is defined as other enantiomorph of the identical basic molecular structure that is substantially free of said compound or midbody or the isomer of diastereomer form.Especially; Term " stereoisomerism is pure " relate to have stereoisomerism excessive at least 80% (be a kind of isomer minimum be 80%; And other possible isomer is at most 20%) to the compound or the midbody of stereoisomerism at the most excessive 100% (being that a kind of isomer is 100% and does not contain other isomer); More particularly; Relate to and have stereoisomerism excessive 90% to 100% compound or midbody at the most, even be more especially and have stereoisomerism excessive 94%, and the most particularly have stereoisomerism excessive 97% to 100% compound or midbody at the most at the most 100%.Term " enantiomer-pure " and " diastereomer is pure " should be understood in a similar fashion, but it then is enantiomeric excess and the diastereomeric excess that has the mixture of being discussed respectively.
The pure stereoisomeric forms in any ratio of The compounds of this invention and midbody can obtain through using program known in the art.For example, can be through enantiomorph is separated from one another with optically active acid or their diastereoisomeric salt of alkali selective crystallization.The example is tartrate, dibenzoyl tartaric acid, YLENE acyl group tartrate and camphorsulfonic acid.Perhaps, can be through adopting the chromatographic technique enantiomer separation of chiral stationary phase.Said pure stereochemistry heterogeneous forms also can be derived from the corresponding pure stereochemistry heterogeneous forms of suitable raw material, and condition is that this reaction stereospecificity takes place.Preferably, if require special steric isomer, then said compound will be synthetic through the stereospecificity preparation method.These methods will advantageously be used the raw material of enantiomer-pure.
The diastereomer racemoid of formula (I) compound can obtain through ordinary method discretely.Suitable physical separation method that can favourable use is for example selective crystallization and chromatography, for example column chromatography.
The present invention also is intended to comprise all isotropic substances of the atom that occurs on the The compounds of this invention.Isotropic substance comprises that those have the same atoms ordinal number but have the atom of different mass number.Through general example and not limited by this, the isotropic substance of hydrogen comprises tritium and deuterium.The isotropic substance of carbon comprises C-13 and C-14.
For therepic use, the salt of formula (I) compound is that wherein gegenion is pharmaceutically acceptable those salt, and this salt can be called as pharmaceutically acceptable bronsted lowry acids and bases bronsted lowry additive salt.But the salt of the pharmaceutically acceptable bronsted lowry acids and bases bronsted lowry of right and wrong also can have been found purposes, for example is used for preparation or the pharmaceutically acceptable compound of purifying.All salt, no matter whether pharmaceutically acceptable, all be included within the scope of the present invention.
Above-mentioned pharmaceutically acceptable bronsted lowry acids and bases bronsted lowry additive salt is intended to comprise the non-toxicity bronsted lowry acids and bases bronsted lowry additive salt form of the therapeutic activity that formula (I) compound can form.Pharmaceutically-acceptable acid addition can be easily through obtaining the s.t. of said alkali form with suitable anionic form.The negatively charged ion that is fit to comprises, for example acetate moiety, Phenylsulfonic acid root, benzoate anion, bicarbonate radical, hydrogen tartrate root, bromide, Ca-EDTA, camphorsulfonic acid root, carbonate, muriate, citrate, dihydrochloride, edetic acid root, ethionic acid root, propionic ester dodecyl sulphate root, ethyl sulfonic acid root, fumaric acid radical, glucoheptose acid group, glucose acid group, glutamate, to hydroxyl kharophen phenylarsonic acid root (glycollylarsanilate), Sucrets root, Hai Baming (hydrabamine), Hydrogen bromide root, salt acid group, hydroxynaphthoic acid root, iodide, hydroxyethylsulfonic acid root, lactate, lactose acid group, malate, maleate, almond acid group, methanesulfonate, MB, methyl nitrate, methyl sulfate, glactaric acid root, naphthene sulfonic acid root, nitrate radical, pounce on acid group (embonate), pantothenate, phosphate radical/hydrogen phosphate, polygalacturonic acid group, salicylate, stearate radical, alkali formula acetate, amber acid radical, sulfate radical, tannic acid root, tartrate anion, 8-Chlorotheophyline root, triethyl iodate thing etc.Otherwise said salt form can be through being converted into free alkali form with suitable alkaline purification.
Formula (I) compound that contains acid proton also can be handled its non-toxic metal or the amine additive salt form of being converted into through the organic and mineral alkali that is fit to cationic form.The basic salt that is fit to comprises those salt that form with organic cation such as dibenzylethylenediamine dipenicillin G, chloroprocaine, choline, diethylolamine, quadrol, meglumine, PROCAINE HCL, PHARMA GRADE etc.; With those salt that form with metallic cation such as aluminium, calcium, lithium, magnesium, potassium, sodium, zinc etc.Otherwise said salt form can be through being converted into free form with suitable s.t..
" N-oxide compound " form of The compounds of this invention is intended to comprise those compounds of one or several nitrogen-atoms in any one triazole ring wherein oxidized (for example one-or two-oxide compound).Can there be (the for example mixture of 1-N-oxide compound, 2-N-oxide compound and 4-N-oxide compound triazole) with single positional isomers or each position different structure mixture form in said nitrogen monoxide.
More than used term " quaternary amine " be defined as; The basic nitrogen of through type (I) compound and the quaternizing agent that is fit to are (for example; Optional substituted alkyl halide, aryl halide or arylalkyl halogenide; Such as methyl iodide or benzyl iodide) between reaction, the quaternary ammonium salt that formula (I) compound can form.Also can use other reactant that has good leavings group, for example trifluoromethanesulfonic acid alkyl ester, methylsulfonic acid alkyl ester and alkyl tosylate.Quaternary amine has a positively charged nitrogen.Pharmaceutically acceptable gegenion comprises cl ions, bromide anion, iodide ion, trifluoroacetic acid root and acetate moiety.The gegenion of selecting can adopt ion exchange resin to introduce.The quaternary amine of formula (I) compound can be through obtaining quaternary ammonium list or disalt acquisition with nitrogen heterocyclic ring (i.e. one or two triazole ring) with the bromoethyl acetate alkylation.
Some formula (I) compound also can tautomeric form exist.Though clearly do not illustrate at above structural formula, these forms all are intended to be included within the scope of the invention.
One embodiment of this invention relates to formula (I) compound, wherein uses one or more following condition:
A) R 1Be hydrogen or C 1-6Alkyl;
B) R 2Be the gonane base or be selected from following group
Figure BPA00001464278600151
C) R 3, R 4And R 5Independently be C separately 6-18Alkyl or gonane base;
D) R 6, R 7And R 8Independently be C separately 1-6Alkyl.
One embodiment of this invention relates to formula (I) compound, wherein uses one or more following condition:
A) R 1Be C 1-6Alkyl;
B) R 2Be the gonane base or
Figure BPA00001464278600152
R in this group 3It is the gonane base.
One embodiment of this invention relates to formula (I) compound and any inferior group (subgroup) thereof, and wherein said gonane base is the cholestane base.
One embodiment of this invention relates to formula (I) compound and any inferior group, wherein R 1It is ethyl.
One embodiment of this invention relates to the salt of formula (I) compound and any inferior group thereof, wherein R 1Be hydrogen, said salt is a sodium salt.
One embodiment of this invention relates to any in the following compounds:
2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base 2-(trimethylammonium ammonium)-ethyl phosphonic acid ester;
2-(acyloxy in the last of the ten Heavenly stems) ethyl 2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base SULPHOSUCCINIC ACID ESTER sodium;
2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base 2-(nonyl oxygen base) ethyl phosphonic acid ester sodium;
2, two (acyloxy in the last of the ten Heavenly stems) the propyl group 2-(2,4 difluorobenzene base)-1 of 3-, 3-two (1H-1,2,4-triazol-1-yl) propane-2-base SULPHOSUCCINIC ACID ESTER sodium;
2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base ethyl (3R, 8R, 9S; 10R, 13S, 14S, 17R)-10,13,17-trimethylammonium-17-((R)-6-methylheptane-2-yl)-2,3; 4,7,8,9,10,11; 12,13,14,15,16,17-ten tetrahydrochysenes-1H-cyclopenta-[a] phenanthrene-3-base SULPHOSUCCINIC ACID ESTER;
2-((2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base oxygen base) (oxyethyl group) phosphorus acyloxy) ethyl (3S, 8R, 9S; 10R, 13S, 14S, 17R)-10,13,17-trimethylammonium-17-((R)-6-methylheptane-2-yl)-2,3; 4,7,8,9,10,11; 12,13,14,15,16,17-ten tetrahydrochysenes-1H-cyclopenta-[a] phenanthrene-3-base succinate;
2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base nonyl SULPHOSUCCINIC ACID ESTER sodium.
The present invention also provides formula (I) compound that a kind of preparation as above defines or the method for its pharmacy acceptable salt, and it comprises with the fluconazole phosphorylation and when needs or in case of necessity the compound that obtains is converted into pharmacy acceptable salt, or vice versa.
Said phosphorylation can be carried out by different way, among the patented claim WO97/28169 (Pfizer Limited) certain methods is provided.A kind of phosphorylation method (a1) can obtain the phosphorous acid ester of formula (III) thus through in suitable reaction medium, making the phosphoramidite reaction of fluconazole and formula (II), and the phosphorous acid ester and the oxidant reaction of said formula (III) are accomplished,
Figure BPA00001464278600161
Wherein
R 1And R 2Each is self-defined the same;
R 9And R 10Independently be separately, optional by C 3-7The substituted C of naphthenic base or phenyl 1-6Alkyl, optional substituted phenyl or C 3-7Naphthenic base; Perhaps R 9And R 10Coupled nitrogen-atoms forms optional substituted 5-or 6-unit saturated heterocyclic together, and wherein said substituting group can be selected from C 1-4Alkyl and phenyl.
Preferred R 9And R 10Independently be C separately 1-6Alkyl, phenyl, perhaps coupled nitrogen-atoms forms the morpholine ring together.
This reaction can sharply influence in the solvent (for example methylene dichloride or THF) of reaction; At weak acid (like tetrazolium, 5-methyl isophthalic acid H-tetrazolium, 1; 2; 4-1H-triazole, pyridine hydrobromide salt or imidazole salts acidifying thing and optional catalytic 4-(dimethylamino) pyridine exist down, under room temperature or higher temperature, carry out.
(peracid for example is such as 3-chloroperoxybenzoic acid or H to make phosphorous acid ester and the oxygenant of the formula (III) that obtains then 2O 2, preferred 30% aqueous hydrogen peroxide solution) react, obtain the SULPHOSUCCINIC ACID ESTER of final formula (I).This reaction can for example in methylene dichloride or the THF, be lower than room temperature at solvent that can sharp influence reaction, for example carries out under 0-20 ℃.
A kind of alternative phosphorylation method (a2) can in acetone, methylene dichloride and salt of wormwood, accomplish chlorinated phosphate (phosphorochloridate) reaction of fluconazole and formula (IV) through at suitable anhydrous response medium.This reaction can at room temperature be carried out.
Figure BPA00001464278600171
Another kind of phosphorylation method (a3) can make fluconazole and PCl in the presence of alkali 3Reaction obtains the midbody compound of formula V thus,
R-O-PCl 2 (V)
Make formula V compound and formula R then 1-OH compound and formula R 2-OH compound reaction realization, wherein
R 1And R 2Each is self-defined the same; And
R is
Figure BPA00001464278600181
Fluconazole and PCl 3Reaction can be at solvent that can sharp influence reaction, for example in methylene dichloride or the THF, in-20 to+20 ℃ of TRs, for example carry out under 0 ℃.The alkali that is fit to comprises pyridine and N-Methylimidazole.
Formula V compound and formula R 1-OH compound and with formula R 2-OH compound (R wherein 1And R 2Defining the same) consecutive reaction of formula (I) compound that as above defined can need not separate under the formula V compound and carry out under the temperature about room temperature.These consecutive reactions can be accomplished with any given order, for example drawing-in system R at first 2-OH compound, and then drawing-in system R 1-OH compound.
For the fluconazole minimization is returned in the hydrolysis of formula (I) end product, final material, form whencesoever, filter cake for example, available washing with acetone is to displace the needed water of this SULPHOSUCCINIC ACID ESTER of hydrolysis.
According to method known to those skilled in the art, can the compound that obtain be chosen wantonly and be converted into pharmacy acceptable salt, or vice versa.
Further, can formula (I) compound be changed each other according to functional group known in the art conversion reaction.For example, can be with amino N-alkylation, be amino with nitroreduction, can convert halogen atom into another kind of halogen.
The pure stereochemistry heterogeneous forms of formula (I) compound can obtain through using methods known in the art.Diastereomer can pass through physical method (for example selective crystallization) to be separated with chromatographic technique such as counter-current distribution, liquid phase chromatography etc.
Formula (I) compound can obtain with the racemic mixture form of enantiomorph, and it can be separated from one another according to method for splitting known in the art.Can be converted into the salt form of corresponding diastereomer with having the racemic formula of enough alkalescence or tart (I) compound through reacting with suitable chiral acid, chiral base respectively.Then, the salt form of said diastereomer is for example separated through selectivity or fractional crystallization, discharge said enantiomorph thus through alkali or acid then.The method of the enantiomerism form of an alternative separate type (I) compound comprises liquid phase chromatography, particularly adopts the liquid phase chromatography of chiral stationary phase.Said pure stereochemistry heterogeneous forms also can be derived from the suitable pure stereochemistry heterogeneous forms of the correspondence of raw material, and prerequisite is that said reaction stereospecificity is carried out.Preferably, if require special steric isomer, then said compound can be synthetic through the stereospecificity preparation method.These methods can be utilized the raw material of enantiomer-pure easily.
The invention still further relates to midbody compound, it can be used for preparation formula (I) compound; Its salt, N-oxide compound, quaternary amine and steric isomer.Thus, the present invention relates to the phosphoramidite and its salt, N-oxide compound, quaternary amine and its steric isomer of formula (II),
R wherein 1, R 2, R 9And R 10Press this paper definition separately.
The invention still further relates to as above phosphorous acid ester and salt, N-oxide compound, quaternary amine and the steric isomer of the formula (III) of definition,
R wherein 1And R 2Press this paper definition separately.
The invention still further relates to as above chlorinated phosphate and salt, N-oxide compound, quaternary amine and the steric isomer of the formula (IV) of definition,
Figure BPA00001464278600193
(IV)
R wherein 1And R 2Press this paper definition separately.
Aspect further one, the present invention relates to formula (VI) chemical group as the purposes of introducing group
Figure BPA00001464278600201
R wherein 1And R 2Press in the embodiment that this paper proposes the definition of any separately; And wavy line (
Figure BPA00001464278600202
Expression) representative and the Sauerstoffatom of medicine combines.
This introducing group is valuable in the further prodrug of other medicinal compound of design (needn't be relevant with fluconazole).
Term " introducing group " is meant through the key that can under specific working conditions, rupture and the medicine functional group of medicine (general and) bonded chemical group, i.e. part.Medicine and the key of introducing between the group can be through enzyme or the fractures of non-enzymatic pathway.Under working conditions, for example give the patient after, medicine and introduce key between the group and can rupture and discharge parent drug.Introduce the fracture of group and can spontaneously carry out (for example passing through hydrolysis reaction), perhaps through another reagent catalysis or induce, for example through enzyme, through light, through acid or through changing or being exposed to physics or environmental parameter, such as the variation of temperature, pH etc.These reagent can be endogenic for the condition of said use, enzyme that for example gives to exist in patient's the body circulation of this prodrug or the acidic conditions in the stomach, and perhaps this reagent can exogenously provide.
The invention still further relates to medicinal compsns, it comprises pharmaceutically acceptable carrier and as compound or its pharmacy acceptable salt of this paper definition of the significant quantity of activeconstituents.
Medicinal compsns of the present invention is parenteral, promptly through the per os administration, for example in intravenously, intramuscular, subcutaneous, intraperitoneal, intraarticular, intralesional (intralesionally), the ventricle, through intraspinal injection, intraosseous infusion or transdermal administration.Medicinal compsns of the present invention also can be in human or animal's brain position, wound site, airtight joint space or body cavity in cabernous sinus, in myocardium inside and outside film or the knurl (intraturnorally) give.
Therefore, can The compounds of this invention be processed the small-volume injection (SVP) that supplies bolus injection or reservoir devices injection or supply the bulk capacity injection (LVP) of venoclysis.Perhaps, through using skin patch, can The compounds of this invention be processed the confession percutaneous drug administration preparation.
Said parenteral administration can adopt such as the suspension in oiliness or the aqueous medium, solution or emulsion form, and can comprise formula agent, like pH regulator agent, complexing agent, isotonic agent, suspension agent, stablizer or dispersion agent.Usually, those vehicle that the intravenous injection typical case uses can be used in the preparation of the present invention, as long as said preparation demonstrates the injection capacity and the acceptable pH scope of suitable viscosity, reduction.
The method that preparation has the various medicinal compsnss of a certain amount of activeconstituents is known to those skilled in the art, perhaps will know understanding according to the disclosure.The relevant instance for preparing the method for medicinal compsns is referring to (Remington; The science and practice of pharmacy (pharmaceutics science with put into practice), Lippincott Williams&Wilkins, the 21st edition, 2006).
Unit dosage can prepare through The compounds of this invention or its pharmacy acceptable salt and sterile media are mixed.Medium according to used is different with concentration, can or be dissolved in the medium said compound suspension.In the preparation solution, can compound dissolution be used for injection and filtration sterilization, suitable phial or the interior also sealing of ampoule of filling people then.Advantageously, will be dissolved in the medium such as the auxiliary of local anesthetic, sanitas and buffer reagent.Be enhanced stability, can freezing behind the said compsn filling medicine bottle and vacuum be removed moisture.Medicinal compsns is rendered as powder type then, and for later use suitable medium dissolves is used aseptic aqueous solution before for example using.Suspension prepares with basic similarly mode, but this compound is suspended in the medium but not is dissolved in the medium, and sterilization can not be accomplished by filtration.Can comprise in the compsn that tensio-active agent or wetting agent are to promote the uniform distribution of said compound.
Injection preparation can be rendered as unit dosage for example in ampoule or in the multi-dose container.
For through skin (for example local) administration purpose, prepare rare aseptic, water-based or part aqueous solution (about usually 0.1%-5% concentration), other aspects are similar to above-mentioned parenteral solution.
Before can using common clinical of medical field by those of ordinary skills, prevention or the treatment significant quantity of treating the needed The compounds of this invention of said medical symptom promptly confirm with clinical method.The said compound that will give or the dosage of its pharmacy acceptable salt depend on individual state, and, can make said dosage be adapted to the symptom of said individual state for reaching best effect according to custom.Therefore; Effect and acting duration that it depends on the frequency and the treatment of administration certainly or prevents compound used in each case, but the responsiveness of the sex of the character that also depends on disease or illness and seriousness and institute's treatment target, age, body weight, the medicine of taking simultaneously and individuality and depend on that said treatment is acute or preventative.The per-cent of the medicine that exists in the preparation also is a factor.Dosage can be adjusted according to weight function and paediatric applications.The instance of the effective dose that preparation of the present invention is used to inject is extremely about 5ml of about 0.1ml, injects once in per 1,2,3,4,5,6 month, and perhaps per 1,2,3 or 4 weeks injection once.The optimizing injection amount is about 2.5ml or following, and for example about 1ml is to about 2.5ml.
The compounds of this invention has purposes, and reason is that they have pharmacological activity in animal (comprising the people).Particularly, said compound can be used for treatment or prevention fungi infestation, comprises yeast infection.For example, they can be used for treating local fungal infection that is caused by Candida, Trichophyton, microsporum or Epidermophyton kind and other organism in the human body or the mucosal infections (for example white mouth and vaginal candidiasis) that is caused by Candida albicans.They also can be used for the systemic fungal infection that treatment is caused by for example Candida (like Candida albicans), Cryptococcus neoformans, Aspergillus flavus, aspergillus fumigatus, coccidioides immitis, secondary coccidioides immitis (Paracoccidiode), histoplasma capsulatum or blastomycete kind.
In addition; Remove the following disease that needs Fluconazole treating; Outside fungemia, respiratory tract mycosis, digestive tube mycosis, urethra mycosis, fungal meningitis, cryptococcal meningitis, onychomycosis, torulosis, the ball mycosis (coccidiomycosis) etc., The compounds of this invention is used in treatment fungoid peritonitis in the deep-seated mycosis medicament.
The compounds of this invention also can be used as oidiomycotic prevention medicament in the immuno-compromised patients, and for example those suffer from patient, organ transplantation patient, AIDS patient or old age or the paediatrics colony of blood property cancer.
Therefore, The compounds of this invention, its pharmacy acceptable salt or its any inferior group useful as drug.Said purposes or treat-ment as medicine comprises the said medicine that gives the amount of the effectively antagonism symptom relevant with fungi infestation, particularly candida infection for the experimenter who infects or experimenter's whole body of being subject to fungi infestation (comprising yeast).
The invention still further relates to the purposes that The compounds of this invention, its pharmacy acceptable salt or its any inferior group are used to prepare prevention or treat the medicine of fungi infestation.In other words, the invention still further relates to formula (I) The compounds of this invention, its pharmacy acceptable salt or its any inferior group that is used to prevent or treat fungi infestation.
The invention still further relates to the method for a kind of prevention or treatment fungi infestation, said method comprises the compound of any inferior group that needs the formula as herein described of the patient of this kind prevention or treatment significant quantity (I) compound, its pharmacy acceptable salt or formula (I) compound.
The invention still further relates to a kind of lipophilic method of fluconazole of improving, this method comprises that said fluconazole is converted into formula (I) compound, its pharmacy acceptable salt or its any Asia to be organized.
In addition, the invention still further relates to a kind of method that fluconazole discharges that prolongs, this method comprises that fluconazole is converted into formula (I) compound, its pharmacy acceptable salt or its any Asia to be organized.
The following example is intended to exemplary illustration the present invention, and does not limit it in this.
Embodiment
Embodiment 1: preparation 2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base 2-(trimethylammonio)-ethyl phosphonic acid ester
Figure BPA00001464278600231
Shown in above flow process 1, at room temperature, in anhydrous methylene chloride; N, N-diisopropylethylamine (H ü nig ' s alkali) exist down, choline chloride 60 and phosphorylation agent cyanoethyl N; The reaction of N-di-isopropyl chloro phosphoramidite; Follow in the presence of tetrazolium and fluconazole (FLC) coupling, use 30% aqueous hydrogen peroxide solution oxidation subsequently, obtain bullion good fortune department fluconazole verivate 1.1 with single stage method.At room temperature, in methyl alcohol, adopt volatile caustic with the fracture of cyanoethyl protection base (two step yields 75%).The phosphodiester that obtains through in methyl alcohol, reacting with aqueous sodium hydroxide solution (0.1M), further is converted into corresponding ammonium phosphate zwitter-ion salt, and yield is 44% behind the chromatography.End product 2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base 2-(trimethylammonio)-ethyl phosphonic acid ester is through proton nuclear magnetic resonance and mass spectrometry, and is as follows:
1H NMR (400MHz, DMSO-d 6): δ 9.00 (s, 2H), 7.60 (s, 2H), 7.07 (m, 1H), 6.86 (m, 1H), 6.61 (m, 1H), 5.50 and 4.91 (the AB system, JAB=14.4Hz, 4H), 4.22 (m, 2H), 3.59 (m, 2H), 3.15 (s, 9H)
MS(ESI)：472(M+H)
Embodiment 2: preparation 2-(acyloxy in the last of the ten Heavenly stems) ethyl 2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base SULPHOSUCCINIC ACID ESTER sodium
Flow process 2
Figure BPA00001464278600251
Shown in above flow process 2, at room temperature, in anhydrous methylene chloride, the reaction in the presence of triethylamine between 1-decanoyl chloride and the terepthaloyl moietie obtains ester OH 2.1 with yield 67%.At room temperature, in anhydrous methylene chloride, at N; N-diisopropylethylamine (H ü nig ' s alkali) exists down, 2.1 with phosphorylation agent cyanoethyl N, the reaction of N-di-isopropyl chloro phosphoramidite; Follow in the presence of tetrazolium and fluconazole (FLC) coupling; Use 30% aqueous hydrogen peroxide solution oxidation subsequently, obtain good fortune department fluconazole verivate 2.2 with single stage method, yield is 44% behind the chromatography.At room temperature, in methyl alcohol, adopt volatile caustic with the fracture of cyanoethyl protection base, yield 99%.The phosphodiester that obtains through in methyl alcohol, further carrying out saponification (100% yield) with aqueous sodium hydroxide solution (0.1M), in methylene dichloride, in the presence of the 4-Dimethylamino pyridine, with positive pelargonyl chloride and triethylamine acidylate, is obtained three second ammonium phosphoric acid salt then.Behind the chromatography, adopt Dowex 50WX8 to carry out cationic exchange, obtain corresponding sodium salt, two step yields are 44%.End product 2-(acyloxy in the last of the ten Heavenly stems) ethyl 2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base SULPHOSUCCINIC ACID ESTER sodium is through proton nuclear magnetic resonance and mass spectrometry, and is as follows:
1H NMR (400MHz, DMSO-d 6): δ 9.00 (s, 2H), 7.55 (s, 2H), 7.05 (m, 1H), 6.87 (m, 1H), 6.59 (m; 1H), 5.55 and 4.87 (the AB system, JAB=14.4Hz, 4H), 4.14 (m, 2H), 3.98 (m, 2H), 2.27 (m; 2H), 1.47 (m, 2H), 1.21 (m, 12H), 0.84 (t, J=6.4Hz, 3H)
MS(ESI)：583(M-H-Na)
Embodiment 3: preparation 2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base 2-(alkoxyl group in the ninth of the ten Heavenly Stems) ethyl phosphonic acid ester sodium
Flow process 3
Figure BPA00001464278600271
Shown in above flow process 3, in backflow toluene, in the presence of tosic acid, adopt the Dean-Stark condition, it is 58% hydroxy ethers 3.1 that the reaction between 1 nonyl alcohol and the terepthaloyl moietie obtains yield.At room temperature, in anhydrous methylene chloride, at N; N-diisopropylethylamine (H ü nig ' s alkali) exists down, 3.1 with phosphorylation agent cyanoethyl N, the reaction of N-di-isopropyl chloro phosphoramidite; Follow in the presence of tetrazolium and fluconazole (FLC) coupling; Use 30% aqueous hydrogen peroxide solution oxidation subsequently, obtain good fortune department fluconazole verivate 3.2 with single stage method, yield is 90% behind the chromatography.At room temperature, in methyl alcohol, adopt volatile caustic with the fracture of cyanoethyl protection base, yield 95%.With the phosphodiester that obtains through in methyl alcohol, being converted into sodium salt, yield 98% with aqueous sodium hydroxide solution (0.1M) reaction.End product 2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base 2-(nonyl oxygen base) ethyl phosphonic acid ester sodium is through proton nuclear magnetic resonance and mass spectrometry, and is as follows:
1H NMR (400MHz, DMSO-d 6): δ 9.01 (s, 2H), 7.55 (s, 2H), 7.05 (m, 1H), 6.88 (m, 1H), 6.60 (m; 1H), 5.55 and 4.87 (the AB system, JAB=14.4Hz, 4H), 3.89 (m, 2H), 3.49 (m, 2H), 3.36 (m; 2H), 1.46 (m, 2H), 1.22 (m, 12H), 0.84 (t, J=6.4Hz, 3H)
MS(ESI)：555(M-H-Na)
Embodiment 4: preparation 2, two (acyloxy in the last of the ten Heavenly stems) the propyl group 2-(2,4 difluorobenzene base)-1 of 3-, 3-two (1H-1,2,4-triazol-1-yl) propane-2-base SULPHOSUCCINIC ACID ESTER sodium
Flow process 4
Figure BPA00001464278600291
Shown in above flow process 4, at room temperature, in anhydrous methylene chloride, in the presence of pyridine, 2-phenyl-1, it is 70% ester 4.1 that the reaction between the pure and mild 1-decanoyl chloride of 3-dioxane-5-obtains yield.Then, palladium hydroxide that employing carbon carries and the hydrogen under the barometric point carry out hydrogenation with compound 4.1, quantitatively obtain glycol 4-2.Then 4-2 and 1-decanoyl chloride carry out single acidylate to obtain yield are 56% primary alconol 4-3.At room temperature, in anhydrous methylene chloride, at N; N-diisopropylethylamine (H ü nig ' s alkali) exists down, compound 4.3 and phosphorylation agent cyanoethyl N, the reaction of N-di-isopropyl chloro phosphoramidite; Follow in the presence of tetrazolium and fluconazole (FLC) coupling; Use 30% aqueous hydrogen peroxide solution oxidation subsequently, obtain good fortune department fluconazole verivate 4.4 with single stage method, yield is 93% behind the chromatography.At room temperature, in methyl alcohol, adopt volatile caustic with the fracture of cyanoethyl protection base, yield 97%.The phosphodiester that obtains through in methyl alcohol, further carrying out saponification (100% yield) by aqueous sodium hydroxide solution (0.1M), in methylene dichloride, in the presence of the 4-Dimethylamino pyridine, by positive pelargonyl chloride and triethylamine acidylate, is obtained three second ammonium phosphoric acid salt then.Behind the chromatography, adopt Dowex 50WX8 to carry out cationic exchange, obtain corresponding sodium salt, two step yields are 34%.End product 2, two (acyloxy in the last of the ten Heavenly stems) the propyl group 2-(2,4 difluorobenzene base)-1 of 3-, 3-two (1H-1,2,4-triazol-1-yl) propane-2-base SULPHOSUCCINIC ACID ESTER sodium is through proton nuclear magnetic resonance and mass spectrometry, and is as follows:
1H NMR (400MHz, DMSO-d 6): δ 8.98 (d, 2H), 7.55 (s, 2H), 7.06 (m, 1H), 6.88 (m, 1H); 6.58 (m, 1H), 5.52 and 4.88 (the AB system, JAB=14.4Hz, 4H), 5.11 (m, X of ABX, 1H); 4.29 with 4.11 (AB of ABX, JAB=12.0Hz, JAX=3.3Hz, JBX=6.7Hz, 2H), 3.93 (m, 2H), 2.26 (m; 4H), 1.48 (m, 4H), 1.22 (m, 24H), 0.84 (t, J=5.8Hz, 6H)
MS(ESI)：767(M-H-Na)
Embodiment 5: preparation 2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base ethyl (3R, 8R, 9S; 10R, 13S, 14S, 17R)-10,13,17-trimethylammonium-17-((R)-6-methylheptane-2-yl)-2,3; 4,7,8,9,10,11; 12,13,14,15,16,17-ten tetrahydrochysenes-1H-cyclopenta-[a] phenanthrene-3-base SULPHOSUCCINIC ACID ESTER
Flow process 5
Shown in above flow process 5, at room temperature, in anhydrous tetrahydro furan; At N, N-diisopropylethylamine (H ü nig ' s alkali) exists down, the phosphorylation agent ethyl n of SUV and new system; The reaction of N-di-isopropyl chloro phosphoramidite is followed in the presence of tetrazolium and fluconazole (FLC) coupling, uses 30% aqueous hydrogen peroxide solution oxidation subsequently; Obtain desired good fortune department fluconazole verivate with single stage method, yield is 76% behind the chromatography.The product that obtains is through proton nuclear magnetic resonance and mass spectrometry, and is as follows:
1H NMR (400MHz, CDCl 3): δ 8.41 (m, 2H), 7.77 (m, 2H), 7.07 (m, 1H), 6.84 (m, 1H), 6.72 (m; 1H), 5.33 (m, 1H), 5.16 (m, 4H), 4.14 (m, 1H), 4.02 (m, 2H); 2.28 (m, 2H), 1.96 (m, 2H), 1.88-0.99 (m, 27H), 0.96 (s, 3H); 0.90 (d, J=10.4Hz, 3H), 0.84 and 0.82 (dd, J=1.5Hz, 6H), 0.64 (s, 3H)
MS(APCI)：783(M)
White powder
Product fusing point DSC characteristic provides in Fig. 1.
Embodiment 6: preparation 2-((2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base oxygen base) (oxyethyl group) phosphorus acyloxy) ethyl (3S, 8R, 9S; 10R, 13S, 14S, 17R)-10,13,17-trimethylammonium-17-((R)-6-methylheptane-2-yl)-2,3; 4,7,8,9,10,11; 12,13,14,15,16,17-ten tetrahydrochysenes-1H-cyclopenta-[a] phenanthrene-3-base succinate
Figure BPA00001464278600321
Shown in above flow process 6, in the backflow methylene dichloride, in the presence of the 4-Dimethylamino pyridine; Making the reaction of SUV and succinyl oxide obtain yield is 55% carboxylic acid 6.1, and it is converted into its acyl chlorides with THIONYL CHLORIDE 97 in toluene under 65 ℃, and at room temperature; In methylene dichloride; In the presence of triethylamine,, obtain yield and be 63% verivate 6.2 further with glycol reaction.At room temperature, in anhydrous tetrahydro furan, at N; N-diisopropylethylamine (H ü nig ' s alkali) exists down, 6.2 with the phosphorylation agent ethyl n of new system, the reaction of N-di-isopropyl chloro phosphoramidite; Follow in the presence of tetrazolium and fluconazole (FLC) coupling; Use 30% aqueous hydrogen peroxide solution oxidation subsequently, obtain desired good fortune department fluconazole verivate with single stage method, yield is 68% behind the chromatography.The product that obtains is through proton nuclear magnetic resonance and mass spectrometry, and is as follows:
1H NMR (400MHz, CDCl 3): δ 8.39 (d, J=14.9Hz, 2H), 7.81 (s, 2H), 7.11 (m, 1H), 6.88 (m, 1H), 6.77 (m, 1H); 5.35 (m, 1H), 5.18 (m, 4H), 4.59 (m, 1H), 4.24 (m, 2H), 4.21-4.01 (m, 4H); 2.61 (m, 4H), 2.30 (m, 2H), 1.98 (m, 2H), 1.83 (m, 2H), 1.62-1.03 (m, 25H); 1.00 (s, 3H), 0.90 (d, J=6.6Hz, 3H), 0.86 and 0.84 (dd, J=1.8Hz, 6H), 0.67 (s, 3H)
MS(APCI)：928(M)
White powder
Product fusing point DSC characteristic provides in Fig. 2.
Embodiment 7: the solubleness of good fortune department fluconazole verivate in medicinal solvent
Table 2 provides in embodiment 1-6 and 14 dissolubility data under each comfortable 25 ℃ in preparation and the final good fortune department fluconazole verivate qualitatively, except that other has explanation, representes with mg/mL.The method of used mensuration solubleness is following: under 25 ℃, with 800rpm, with the suspension rotation jolting of 6mg good fortune to be measured department fluconazole verivate in the medicinal solvent that 500 μ l are suitable for 24 hours.The good fortune department fluconazole derivative solution that this is saturated filters (0.45 μ m), and 150 μ l filtrating is diluted with methyl-sulphoxide (50 μ l DMSO).This solution is made an experiment, and each is tested three times and carries out, and measures (LCMS, 1 μ l and 10 μ l injection volumes) through liquid chromatography-mass spectrography.Be dissolved in preparation standard liquid among the DMSO (1mg/ml) through good fortune department fluconazole verivate with correspondence.For measuring solubleness, adopt the identical LCMS condition of above exemplary sample to inject four sample sizes (0.5,1,2,4 μ l) standardized solution.
Table 2
Figure BPA00001464278600331
Figure BPA00001464278600341
aHydroxypropyl-beta-cyclodextrin-HPBCD
bA kind of emulsifying agent, it is provided by BASF AG (Germany) commerce through making 45 moles of ethylene oxide and 1 mole of THIXCIN prepared in reaction.
cCaprylic/capric triglyceride is provided by SASOL GmbH (Germany) commerce.
Table 3
Figure BPA00001464278600342
What the value in table 3 bracket was corresponding is the fluconazole concentration of being calculated of considering the molecular weight of relevant good fortune department's fluconazole prodrug and fluconazole itself.
Embodiment 8: the fluconazole verivate 2-of good fortune department (2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base 2-(the trimethylammonio)-chemicalstability of ethyl phosphonic acid ester in medicinal solvent
Table 4 is provided at the chemicalstability data in some medicinal solvent, representes (%w/w) with the weight percentage that embodiment residual in the solution after certain period 1 prepares also final qualitatively good fortune department fluconazole verivate.This test is carried out 2 times, and said residual weight % measures through liquid chromatography-mass spectrography (LCMS).
Table 4
Figure BPA00001464278600343
Figure BPA00001464278600351
Table 4 shows after 14 days that at the most 1% said good fortune department fluconazole verivate does not remain in the relevant aqueous solution or hydroxypropyl-beta-cyclodextrin or the polyglycol solution.
Embodiment 9: the fluconazole verivate 2-of good fortune department (acyloxy in the last of the ten Heavenly stems) ethyl 2-(2,4 difluorobenzene base)-1,3-two (1H-1,2, the 4-triazol-1-yl) propane-chemicalstability of 2-base SULPHOSUCCINIC ACID ESTER sodium in medicinal solvent
Table 5 is provided at the chemicalstability data in some medicinal solvent under 25 ℃, representes (%w/w) with the weight percentage that embodiment residual in the solution after certain period 2 prepares also final qualitatively good fortune department fluconazole verivate.This test is carried out 2 times, and said residual weight % measures through liquid chromatography-mass spectrography (LCMS).
Table 5
Figure BPA00001464278600352
Table 5 shows after 14 days that about at the most 2% said good fortune department fluconazole verivate does not remain in the relevant aqueous solution or hydroxypropyl-beta-cyclodextrin or the polyglycol solution.
Embodiment 10: the fluconazole verivate 2-of good fortune department (2,4 difluorobenzene base)-1,3-two (1H-1,2, the 4-triazol-1-yl) propane-chemicalstability of 2-base 2-(nonyl oxygen base) ethyl phosphonic acid ester sodium in medicinal solvent
Table 6 is provided at the chemicalstability data in some medicinal solvent under 25 ℃, representes (%w/w) with the weight percentage that embodiment residual in the solution after certain period 3 prepares also final qualitatively good fortune department fluconazole verivate.This test is carried out 2 times, and said residual weight % measures through liquid chromatography-mass spectrography (LCMS).
Table 6
Figure BPA00001464278600361
Table 6 shows after 14 days that about at the most 5% said good fortune department fluconazole verivate does not remain in the relevant aqueous solution or hydroxypropyl-beta-cyclodextrin or the polyglycol solution.
Embodiment 11: good fortune department fluconazole verivate 2, two (acyloxy in the last of the ten Heavenly stems) the propyl group 2-(2,4 difluorobenzene base)-1 of 3-, 3-two (1H-1,2, the 4-triazol-1-yl) propane-chemicalstability of 2-base SULPHOSUCCINIC ACID ESTER sodium in medicinal solvent
Table 7 is provided at the chemicalstability data in some medicinal solvent, representes (%w/w) with the weight percentage that embodiment residual in the solution after certain period 4 prepares also final qualitatively good fortune department fluconazole verivate.This test is carried out 2 times, and said residual weight % measures through liquid chromatography-mass spectrography (LCMS).
Table 7
Figure BPA00001464278600362
Table 7 shows except that in the water of pH 10, and about at the most 12% said good fortune department fluconazole verivate does not remain in the relevant aqueous solution or hydroxypropyl-beta-cyclodextrin or the polyglycol solution after 14 days.
Embodiment 12: the fluconazole verivate 2-of good fortune department (2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base ethyl (3R, 8R, 9S; 10R, 13S, 14S, 17R)-10,13,17-trimethylammonium-17-((R)-6-methylheptane-2-yl)-2,3; 4,7,8,9,10,11; 12,13,14,15,16,17-ten tetrahydrochysenes-1H-cyclopenta-[a] phenanthrene-chemicalstability of 3-base SULPHOSUCCINIC ACID ESTER in medicinal solvent
Table 8 is provided at the chemicalstability data in some medicinal solvent, representes (%w/w) with the weight percentage that embodiment residual in the solution after certain period 5 prepares also final qualitatively good fortune department fluconazole verivate.This test is carried out 2 times, and said residual weight % measures through liquid chromatography-mass spectrography (LCMS).
Table 8
Figure BPA00001464278600371
Table 8 shows except that in the water of pH 2, and about at the most 8% said good fortune department fluconazole verivate does not remain in the hydroxypropyl-beta-cyclodextrin solution after 14 days.
Embodiment 13: the fluconazole verivate 2-of good fortune department ((2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base oxygen base) (oxyethyl group) phosphorus acyloxy) ethyl (3S, 8R, 9S; 10R, 13S, 14S, 17R)-10,13,17-trimethylammonium-17-((R)-6-methylheptane-2-yl)-2,3; 4,7,8,9,10,11; 12,13,14,15,16,17-ten tetrahydrochysenes-1H-cyclopenta-[a] phenanthrene-chemicalstability of 3-base succinate in medicinal solvent
Table 9 is provided at the chemicalstability data in some medicinal solvent, representes (%w/w) with the weight percentage for preparing also final qualitatively good fortune department fluconazole verivate among the embodiment residual in the solution after certain period 6.This test is carried out 2 times, and said residual weight % measures through liquid chromatography-mass spectrography (LCMS).
Table 9
Figure BPA00001464278600372
Table 9 shows except that in the water of pH 2, and about at the most 13% said good fortune department fluconazole verivate does not remain in the hydroxypropyl-beta-cyclodextrin solution after 14 days.
Embodiment 14: preparation 2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base nonyl SULPHOSUCCINIC ACID ESTER sodium
Figure BPA00001464278600381
Shown in above flow process 7, in first step, at room temperature, in dichloromethane solvent, at N, N-diisopropylethylamine (H ü nig ' s alkali) exists down, makes nonane-1-alcohol and structural formula (C 3H 7) 2N-P (Cl)-O-(CH 2) 2The phosphoramide verivate of-CN representative; Promptly (3-[chloro-[two (propane-2-yl) amino] phosphine base] oxygen base propionitrile) reacts; Then at room temperature; In the presence of tetrazolium, add fluconazole, at room temperature add the aqueous hydrogen peroxide solution or the tert-butyl peroxide aqueous solution at last, be converted into fluconazole verivate 14.1 thus.This step reaction yield is 73%.
Then, through at room temperature, in methanol solvate,, said fluconazole verivate 14.1 is converted into fluconazole verivate 14.2 with the ammoniacal liquor reaction.This step reaction yield is 95%.In further step, latter's fluconazole verivate 14.2 through at room temperature in methanol solvate, reacting with aqueous sodium hydroxide solution (0.1M), is converted into corresponding ammonium phosphate zwitter-ion salt.This step reaction yield is 86%.End product 2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl) propane-2-base nonyl SULPHOSUCCINIC ACID ESTER sodium is through proton nuclear magnetic resonance and mass spectrometry, and is as follows:
1H NMR (400MHz, DMSO-d 6): peak position is at 9.05 (s), 7.54 (s), 7.06 (m), 6.84 (m), 6.60 (m), 5.56,4.85,3.77 (m), 1.51 (m), 1.23 (s) and 0.84 (t) ppm, and MS:513 (M+H-Na), 511 (M-H-Na).
Embodiment 15: the fluconazole verivate 2-of good fortune department (2,4 difluorobenzene base)-1,3-two (1H-1,2, the 4-triazol-1-yl) propane-chemicalstability of 2-base nonyl SULPHOSUCCINIC ACID ESTER sodium in medicinal solvent
Table 10 is provided at the chemicalstability data in some medicinal solvent, representes (%w/w) with the weight percentage for preparing also final qualitatively good fortune department fluconazole verivate among the embodiment residual in the solution after certain period 14.This test is carried out 2 times, and said residual weight % measures through liquid chromatography-mass spectrography (LCMS).
Table 10
Figure BPA00001464278600391
Table 10 shows after 14 days that 0.6% said fluconazole verivate does not remain in the relevant aqueous solution or hydroxypropyl-beta-cyclodextrin or the polyglycol solution at the most.

Claims (17)

1. formula (I) compound and salt thereof, N-oxide compound, quaternary amine and steric isomer:
Wherein:
R 1Be hydrogen or C 1-6Alkyl;
R 2Be the gonane base or be selected from following group
Figure FPA00001464278500012
Symbol
Figure FPA00001464278500013
Represent C 2-6Alkylidene group;
R 3, R 4And R 5Independently be C separately 6-18Alkyl or gonane base; With
R 6, R 7And R 8Independently be C separately 1-6Alkyl.
2. the compound of claim 1, wherein R 2Be the gonane base or be selected from following group:
Figure FPA00001464278500021
3. the compound of claim 1, wherein
R 2Be gonane base or group In this group, R 3It is the gonane base.
4. each compound among the claim 1-3, wherein said gonane base is the cholestane base.
5. each compound, wherein R among the claim 1-4 1It is ethyl.
6. the salt of each compound, wherein R among the claim 1-4 1Be that hydrogen and said salt are sodium salts.
7. medicinal compsns, it comprises pharmaceutically acceptable carrier and as each compound or its pharmacy acceptable salt among the claim 1-6 of the significant quantity of activeconstituents.
8. the medicinal compsns of claim 7, wherein in this medicinal compsns intravenously, intramuscular, subcutaneous, intraperitoneal, intraarticular, intralesional, the ventricle, through intraspinal injection, intraosseous infusion or transdermal administration.
9. each compound or its pharmacy acceptable salt among the claim 1-6, it is used as medicine.
10. the purposes that each compound or its pharmacy acceptable salt are used to prepare prevention or treat the medicine of fungi infestation among the claim 1-6.
11. each compound or its pharmacy acceptable salt among the claim 1-6, it is used for prevention or treatment fungi infestation.
12. the method for prevention or treatment fungi infestation, it comprises among the claim 1-6 that needs the patient of this kind prevention or treatment significant quantity each compound or its pharmacy acceptable salt.
13. one kind prepares among the claim 1-6 each formula (I) compound or the method for its pharmacy acceptable salt, it comprises:
A1) in suitable reaction medium, make the phosphoramidite reaction of fluconazole and formula (II), obtain the phosphorous acid ester of formula (III) thus, further make the phosphorous acid ester and the oxidant reaction of said formula (III) then; Perhaps
Figure FPA00001464278500031
A2) in suitable anhydrous response medium, make the chlorinated phosphate reaction of fluconazole and formula (IV); Perhaps
Figure FPA00001464278500032
A3) in the presence of alkali, make fluconazole and PCl 3Reaction obtains the midbody compound of formula V thus,
R-O-PCl 2 (V)
And make formula V compound and formula R 1-OH compound and formula R 2The reaction of-OH compound; With
B) optional the compound that generates is converted into pharmacy acceptable salt or vice versa;
Wherein
R 1And R 2Separately by definition in the claim 1;
R 9And R 10Independently be optional separately by C 3-7The substituted C of naphthenic base or phenyl 1-6Alkyl, optional substituted phenyl or C 3-7Naphthenic base; Perhaps R 9And R 10Coupled nitrogen-atoms forms optional substituted 5-or 6-unit saturated heterocyclic together, and wherein said substituting group can be selected from C 1-4Alkyl and phenyl; With
R is
14. phosphoramidite, the phosphorous acid ester of formula (III) or the chlorinated phosphate of formula (IV) by the formula (II) of definition in the claim 13.
15. formula (VI) chemical group is as the purposes of introducing group
Figure FPA00001464278500042
R wherein 1And R 2Separately by definition in the claim 1; With
Combining of the Sauerstoffatom of wavy line (
Figure FPA00001464278500043
expression) representative and medicine.
16. a lipophilic method of improving fluconazole, it comprises compound or its pharmacy acceptable salt that said fluconazole is converted among the claim 1-6 each.
17. a method that prolongs the release of fluconazole, it comprises compound or its pharmacy acceptable salt that said fluconazole is converted among the claim 1-6 each.
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